High frequency stimulation of selected brain nuclei has provided dramatic benefit for people with Parkinson disease (PD) and essential tremor (ET). Stimulation of the ventral intermediate nucleus (VIM) of the thalamus may abolish contralateral tremor in people with ET or PD. Bilatera'' stimulation of the subthalamic nuclei (STN) in people with PD markedly decreases slowness, stiffness, tremor and reduces the need for dopamimetic therapy. Despite these remarkable benefits, the mechanism of action of deep brain stimulation (DES) remains unknown Some investigators have proposed that DBS reduces efferent neuronal firing by either increased inhibition or conduction block. Alternatively, DBS could increase efferent activity, as suggested by our preliminary data and the work of others. We hypothesize that DBS in VIM or STN works by stimulating projection neurons that can be identified by increased blood flow at their terminal fields. We further propose that STN stimulation produces changes in motor behavior or working memory that reflect stimulation of specific brain regions such as supplementary motor area or dorsolateral prefrontal cortex. We plan to use positron emission tomography (PET) to measure blood flow responses to DBS of VIM in ET patients using subtraction image analysis. We will determine whether local blood flow increases or decreases at the sites of the terminal fields of efferent neurons that project from VIM (in ET patients) or STN (in PD patients). We also will vary stimulus variables to produce graded reductions in tremor amplitude and use these different responses to identify regional brain responses that correlate with the clinical effect. In PD patients, we will quantify STN DBS-induced changes in bradykinesia, rigidity, tremor and working memory and correlate them with regional blood flow responses. These studies will permit us to determine whether deep brain stimulation works by driving efferent neurons (cell bodies, axons or both). Further, these investigations will reveal new insights into the mechanisms of how DBS of VIM reduces tremor and how DBS of STN reduces bradykinesia, rigidity, tremor and working memory. Such information may help to optimize treatment with this new modality and potentially suggest alternate approaches to provide additional clinical benefit.